celecoxib, Celebrex
Celecoxib and difluoromethylornithine in combination have strong therapeutic activity against UV-induced skin tumors in mice.

Fischer SM, Conti CJ, Viner J, Aldaz CM, Lubet RA.

The University of Texas M.D.Anderson Cancer Center, Science Park-Research Division, PO Box 389, Park Road 1C, Smithville 78957, USA. sa83161 odin.mdacc.tmc.edu

The cyclooxygenase-2 (COX-2) inhibitor celecoxib and the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) were each previously shown to prevent skin tumor development when administered throughout the course of UV irradiation. This raised the question of whether maintenance or continued growth of existing tumors required prostaglandins, the product of COX, or polyamines, the product of ODC. To address this question, SKH hairless mice were irradiated 3 times/week with 90 mJ/cm(2); this dose was increased 10% weekly to a maximum of 175 mJ/cm(2). UV was stopped at 27 weeks, at which time there were an average of 5 papillomas/mouse. The mice were then placed in one of four treatment groups: group 1, no treatment; group 2, 0.4% DFMO in the drinking water; group 3, 500 p.p.m. celecoxib in the diet (AIN76); group 4, both DFMO and celecoxib. The control group continued to produce new tumors in a nearly linear manner such that by week 31 the tumor number had nearly doubled, i.e. approximately 10 tumors/mouse. The group receiving DFMO showed significant tumor regression, losing an average of 1 tumor/mouse/week, such that 50% of the tumors remained at week 31. The celecoxib group showed a 25% reduction in tumor number. The group receiving the combination of celecoxib and DFMO showed the greatest regression, with an 89% reduction in tumor number compared with the control group. There was also a corresponding reduction in the size of the tumors. To determine whether tumor regression was permanent or required continued treatment, all treatments were stopped at 31 weeks. Over the next 4 weeks, tumors reappeared at the same rate in all treatment groups. It is concluded that the combination of celecoxib and DFMO are potent therapeutic agents for skin cancer, although the benefits are lost with the cessation of treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12771040&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin.

Chun KS, Kim SH, Song YS, Surh YJ.

College of Pharmacy, Seoul National University, Seoul, Korea.

Celecoxib, the first US FDA-approved selective cyclooxygenase-2 (COX-2) inhibitor initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, was reported to reduce the polyp burden in patients with familial adenomatous polyposis. This specific COX-2 inhibitor also protects against experimentally induced carcinogenesis, but molecular mechanisms underlying its chemopreventive activities remain largely unresolved. In the present work, we found that celecoxib inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of COX-2 in female ICR mouse skin when applied topically 30 min prior to TPA as determined by both immunoblot and immunohistochemical analyses. In another study, celecoxib attenuated the DNA binding activity of activator protein 1 (AP-1) through suppression of c-Jun and c-Fos expression in TPA-treated mouse skin. In addition, celecoxib inhibited both the catalytic activity and phosphorylation of p38 mitogen-activated protein (MAP) kinase. In the same animal model, TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and p38 MAP kinase, which are upstream of AP-1 in mouse skin. In order to clarify the roles of p38 and ERK in TPA-induced AP-1 activation, we utilized the pharmacologic inhibitors of these enzymes. The p38 inhibitor SB203580 blocked TPA-mediated AP-1 activation, while the MEK1/2 inhibitor U0126 was not inhibitory despite suppression of c-Fos expression in mouse skin. Furthermore, SB203580 markedly inhibited COX-2 expression induced by TPA. Taken together, these findings suggest that celecoxib down-regulates COX-2 by blocking activation of p38 MAP kinase and AP-1, which may represent molecular mechanisms underlying antitumor promoting effects of this drug on mouse skin tumorigenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14729583&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of celecoxib through human skin.

Yener G, Gonullu U, Uner M, Degim T, Araman A.

Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Turkey. gulyen superonline.com

The aim of this study was the comparison of three different formulations (gel, o/w emulsion, oleagenous cream) and two penetration enhancers (oleic acid and menthol) as vehicle systems for celecoxib in respect of release and penetration through excised human skin in vitro. The influence of the vehicle on the release rate was studied in vitro using a cellulose acetate membrane. The release rate could be increased by up to 6.5 and 2.5 times with gel and o/w emulsion compared to oleagenous cream respectively. Further in vitro penetration measurements using human skin on Franz diffusion cells were performed with and without oleic acid and menthol as enhancers. It was shown that the penetration rate is strongly dependent upon the enhancer type and concentration but not on the vehicle itself and could be increased by 48% when 5% oleic acid was used in oleagenous cream. In all formulations tested, celecoxib was released and penetrated into human skin more quickly and to a greater extent from the gel formulations. There is no topical formulation available of celecoxib and its penetration properties through human skin have not been investigated. Since celecoxib creates some gastrointestinal disturbances, topical formulations of celecoxib preferably in gel form including 5% oleic acid could be suggested as an alternative.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12779049&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effects of nonsteroidal anti-inflammatory drugs on prostacyclin and thromboxane in the kidney.

Lomnicka M, Karouni K, Sue M, Wessel LA, Bing RJ.

Department of Experimental Cardiology, Huntington Medical Research Institutes, Pasadena, California 91101, USA.

Dose-response curves were obtained relating the effects of increasing amounts of aspirin, a nonselective cyclooxygenase (COX) inhibitor, and celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, on the concentrations of prostacyclin and thromboxane in renal cortex and medulla of rabbits. The concentrations of the two agonists (aspirin and celecoxib) which elicit a half-maximal response on the prostanoid concentration (EC(50)) were compared. Additionally, controls for prostacyclin and thromboxane were related to values for the experimental groups. The EC(50) values for celecoxib were considerably lower than those for aspirin, indicating that celecoxib was more effective in suppressing prostanoid production. There were also significant differences between the majority of experimental groups and their respective controls, further evidence for the greater inhibitory activity of celecoxib on prostacyclin. Celecoxib lowered the ratio prostacyclin/thromboxane in the renal medulla; mercuric chloride further diminished the concentration of prostacyclin in the renal medulla. The results confirm that in the normal rabbit kidney, both nonselective and specific COX inhibitors interfere with renal prostanoid synthesis, but that a selective COX-2 inhibitor is more effective. Copyright 2003 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12784086&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheumatoid arthritis.

Maetzel A, Krahn M, Naglie G.

University Health Network, Toronto, Ontario, Canada. maetzel uhnres.utoronto.ca

OBJECTIVE: To evaluate the cost effectiveness of the cyclooxygenase 2 (COX-2) selective nonsteroidal antiinflammatory drug (NSAID) rofecoxib compared with naproxen and the COX-2 NSAID celecoxib compared with ibuprofen and diclofenac. METHODS: Cost-effectiveness analysis based on a 5-year Markov model. Probability estimates were derived from detailed data of 2 randomized trials and a systematic search of the medical literature. Utility estimates were obtained from 60 randomly selected members of the general public. Cost estimates were obtained from Canadian provincial databases. Incremental cost-effectiveness ratios were calculated for patients at average risk of upper gastrointestinal (UGI) events and for high-risk patients with a prior history of a UGI event. Subjects were patients with osteoarthritis or rheumatoid arthritis (RA) where a decision has been made to treat with NSAIDs but who do not require low-dose aspirin. Main outcome measures were proportion of patients with clinical or complicated UGI events, quality-adjusted life expectancy, and life expectancy. RESULTS: Evaluation of rofecoxib versus naproxen in patients with RA at average risk resulted in costs per quality-adjusted life year (QALY) gained of $Can271,188. Celecoxib was dominated by diclofenac in average-risk patients. Both rofecoxib and celecoxib are cost-effective in high-risk patients. Analyses by age groups and assuming a threshold of Can$50,000 per QALY gained, suggest that rofecoxib or celecoxib would be cost-effective in patients aged over 76 and 81, respectively, without additional risk factors. CONCLUSION: Both rofecoxib and celecoxib are economically attractive in high risk and elderly patients. They are not economically attractive in patients at average risk. Coprescription of proton-pump inhibitors with COX-2 NSAIDs is not economically attractive for patients at high risk.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12794781&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The cox-2-specific inhibitor celecoxib inhibits adenylyl cyclase.

Saini SS, Gessell-Lee DL, Peterson JW.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1070, USA.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known causes of acute renal insufficiency and gastropathy in patients with chronic inflammatory diseases. This action is presumed to result from nonselective inhibition of both constitutive and inducible forms of prostaglandin H synthases, also known as the cyclooxygenase enzymes (i.e., COX-1 amd COX-2). Celecoxib (Celebrex) is a COX-2 enzyme inhibitor and has emerged as a preferred therapeutic agent for the treatment of rheumatoid arthritis as compared to other NSAIDs. Celecoxib has recently been the subject of criticism for its side effects, mainly arterial thrombosis and renal hemorrhage, although it is considered a superior drug in protecting the gastrointestinal tract. In the present study, we report that celecoxib not only inhibited COX-2, but also exhibited the property of inhibiting adenylyl cyclase, an important enzyme forming the intracellular second messenger 3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Celecoxib also inhibited cholera toxin-stimulated cAMP formation, which indicated its ability to permeate cell membranes in order to reach intracellular adenylyl cyclase. It inhibited in vitro adenylyl cyclase activity in both human colonic epithelial cells and purified adenylyl cyclase from Bordetella pertussis. The IC50 of celecoxib for B. pertussis adenylyl cyclase was calculated to be 0.375 mM. Lineweaver-Burk analysis showed that the type of enzyme inhibition was competitive. The apparent Km and Vm of adenylyl cyclase was calculated as 25.0 nM and 7.14 nmol/min/mg, respectively. Celecoxib changed the Km value to 66.6 nM without affecting the Vmax. The current study suggests that apart from inflammation, celecoxib therapy could be further extended to diseases involving cAMP upregulation either by endogenous reactions or exogenous agents. These new data showing inhibition of adenylyl cyclase should be considered in light of the drug's pathological effects or in patients specifically excluded from treatment (e.g., asthmatics).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12797547&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Synergy between celecoxib and radiotherapy results from inhibition of cyclooxygenase-2-derived prostaglandin E2, a survival factor for tumor and associated vasculature.

Davis TW, O'Neal JM, Pagel MD, Zweifel BS, Mehta PP, Heuvelman DM, Masferrer JL.

Oncology Discovery Research, Pfizer Corporation, St. Louis, Missouri 63017, USA.

Previous work has demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors can act synergistically with radiotherapy to improve tumor debulking and control in preclinical models. The underlying mechanism of this remarkable activity has not yet been determined. Here, we report that radiation can elevate intratumoral levels of COX-2 protein and its products, particularly prostaglandin E(2) (PGE(2)). Furthermore, inhibition of COX-2 activity or neutralization of PGE(2) activity enhances radiotherapy even in tumors where COX-2 expression is restricted to the tumor neovasculature. Direct assessment of vascular function by direct contrast enhancement-magnetic resonance imaging showed that the combination of radiation and celecoxib lead to enhanced vascular permeability. These observations suggest that an important mechanism of celecoxib-induced radiosensitization involves inhibition of COX-2-derived PGE(2), thus removing a survival factor for the tumor and its vasculature.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14729635&dopt=Abstract celecoxib, Celebrex